The gastro-intestinal lumen is massively colonized by bacteria and for most metazoans this relationship is mutually beneficial. The epithelial cell barrier is essential for the symbiosis of prokaryotes and eukaryotic hosts, as it creates a boundary necessary for coexistence by preventing mucosal inflammation in response to bacterial or other luminal stimuli. However, in some individuals this balance is upset, resulting in persistent gastro-intestinal inflammation (IBD), that manifests itself in two major diseases, Crohn's disease and ulcerative colitis (UC), and may well also contribute to Irritable Bowel Syndrome (IBS).
Garrett et al. (Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33-45 (2007)) have developed a robust mouse model of ulcerative colitis whose pathologic features and response to anti-TNF treatment closely resemble the human disease. It was found that deficiency of a particular regulatory gene in the innate immune system (resulting from a double knock out of the genes T-bet & RAG2; named TRUC for T-bet RAG2 Ulcerative Colitis) resulted in aggressive, spontaneous, and communicable UC and increased susceptibility to colitis in immunologically intact hosts. The pathogenesis of the disease was mapped to the excessive production of the pro-inflammatory cytokine, TNF-α in dendritic cells in the colon. The mucosal immune system displayed a hyperactive response by overproducing TNF-α in colonic dendritic cells, a cytokine that is cytotoxic for gastro-intestinal epithelial cells. The ensuing breach of the colonic epithelial barrier led to a shift in the commensal bacterial population to a colitogenic flora. This colitogenic flora could then be transmitted both vertically and horizontally to genetically intact hosts.